Process for the preparation of thiophene dicarboxylic acid



Unit stateslatfint o PROCESS FOR THE PREPARATION OF THIOPHENE DICARBOXYLIC ACID Reuben Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing." Original application June 30, 1950, Serial Not=171,555.- Divided and this application July 29,

1955, SerialNo. 525,352 1 I 5 Claims. (c1. 260-3312 This invention relates tonew chemical compounds and to their preparation, and more particularly to certain 5- membered heterocyclic compounds, to novel substituted succinic compounds cyclized to. form the said heterocyclic compounds, and to the synthetic methods employed in producing thesuccinic and heterocyclic compounds.

,Jones and Edmund c. Kornfeld, Indianapolis,

This application is a division of our copending applica l tion Serial No. 171,555, filed June 30, 1950.

The compounds and processes of this invention are il-.

lustrated by the following formulas, in which R represents an esterifying radical, and R1 represents a lower alkyl" mediates in organic chemical synthesis. The thiophenes.

are useful in the synthesis of substances'having biotin or antibiotinactivity, and the pyrroles have utility in the synthesisof compounds of the character of hemin and chlorophyll. p I To illustrate the excellence of the synthesis of the heterocyclic componds disclosed herein, reference is made to the methods of preparation of furan compounds previously known to the art, as exemplified by the publications of Reichstein et al. [Helv. Chim.-Acta. 16, 276 (1933)], and Alderet al. EBer. der Deut. Chem. Gesell. 70B, 1354 (1937 )1. The methods of those published articlesrequire starting materials which are expensive and diflicult to obtain. Moreover, the synthetic methods themselves areinconvenient and difiicult to carry out. In sharp:con-' trast thereto, the synthetic methods provided'by the present invention are easily carried out with simple and readily available starting materials; I 1-.

dicarboxy-substituted furan con'ti The key to the successful synthesis of 'theabove-defined.

heterocyclic compounds resides in the provision of a new ester, a 1-formyl-2-dialkoxymethylsuccinic acid ester.

This new style of ester is represented by the followingf ormula aooc-o-onoooa H on dmoinn j in which R and R1 have the'saine significance hereinabove. r

The l y succinic acid esterlii s' obtained by either of two methods, ('1) A dialkylforfmyl succinic acid ester is converted to a dialkyl-dialkoxymethyl succinic acid ester by reacting the former with ay kylorthoformate, and the dialkoxy compound is formylated with an alkylformate in the presence of an alkali; (2.)

a dialkylforrnyl succinic acid ester is reacted with an al; cohol in the presence of an acid catalyst to obtain a dialkyl-dialkoxy nethyl succinic acid ester which is formyk' ated as in method 1 above.

' The 1-formyl2dialkoxymethyl succinic acid ester can have as esterifying groups any. of the esterifying groups commonly employed for such purposes. For reasons of convenienceand economy, it is preferable to employv lower alkyl radicals as esterifying groups. It will be obvious flzto those skilled in the art thatshould other esterifying' groups be employed they should not contain groups e. g.,

OI-I, -NH2, etc., which would'interfere withthe desired condensation reaction.

[The alkylorthoformate employed can be any convenient and readily available alkylorthoformate, examples of The cyclizing agent to be used in combination with the such being methyl, ethyl, propyl, etc, orthoforrnates.

In the course of the preparation of the diethyl-l-formyl-Z-dialkoxymethyl succinic acid esters there is a possibility of ester exchange when the esterifying group of the alkyl-orthoformate"differs from that of the succinic acid diester. Accordingly, when it is desired to produce di rectly a 3,4-heterocyclic dicarboxylic acid ester which unquestionably contains the desired esterifying radicals on the carboxy groups, the alkylorthoformate employed in the synthesis of theintermediate succinic acid ester should contain the same esterifying radical as that contained in the succinic acid 'diester. However, when the compound to be produced is to be the dicarboxy acid the precautions against ester exchange can be disregarded.

dialkoxymethyl succinic acid ester to produce the 3,4-dicarboxy-substituted heterocyclic compound is an acidic cyclizing agent and is chosen with respect to its ability to cause (A) a simple cyclization of the succinic acid ester} in which case the furan heterocyclic compound is produced; or (B) its ability tocause simultaneous cyclization and substitution, in which case a thiophene or pyrrole heterocyclic compound is produced. Suitable cyclizing agents capable of producing the furan heterocyclic compound ini clude agents such as sulfuric acid, phosphoric acid, phosphorus oxyc hloride, hydrogen chloride, boron trifiuoride,

zinc chloride, andthe like. Cyclizing agents which cause cyclization'and substitution to produce a thiophe'ne com pound include phosphoruspentasulfide and the like. Cy-

'- clizinglagents which" cause simultaneous cyclization and substitution to produce'apyrrole compound include agents such 'as ammonium chloride, ammonium acetate and other like ammonium-containing agents. l

The heterocyclic dicarboxylic acid diesters thus prepared are readily hydrolyzed by the common methods of the art to produce 3,4'heterocyclic dicarboxylic acids.-

Suitable hydrolytic methods include treating the esters with aqueous alkali, followed by acidification and recovcry of the free; acid, and the like. The 3,4-heterocyclic'di-' carboxylicacidstthus obtainedcan be re-esterified by cus-= vl atented May tomary esterifying methods well known to the art to produce other esters.

The following examples illustrate the preparation of certain of the novel compounds of this invention and the processes employed in producing them.

EXAMPLE 1 Preparation of diethyl'1-formyl-2 diethoxymethylsuccinate A mixture of 700 g. (4.0'mols) of diethyl succinate and 370 g. (5.0 mols) of ethyl formate was added to a wellstirred suspension of 100 g. (4.3 mole) of finely divided sodium in 2 liters of anhydrous ether. The reaction mixture, was allowed to stand overnight at room temperature, and then 1.5 liters ofice water were added. The aqueous layer was separated from the ether layer and acidified with cold 12.N sulfuric acid, whereupon diethyl formylsuccinate separated as an oill The aqueous layer was removed and extracted with500 cc. of ether to extract an additional amount of diethyl formylsuccinate, and the ether extract and the oily diethyl formyl succinate were combined, dried with anhydrous magnesium sulfate, and distilled The fraction boiling at 120-135 C. at mm. pressure, comprising diethyl formylsuccinate, was collected.

A mixture of 1100 g. (5.4 mols) of diethyl formylsuccinate, 850 g. (5.75 mols), ofethylorthoformate and 350 cc. of absolute alcohol was prepared. To the mixture were. added 3 dropsof concentrated sulfuric acid, whereupon the. reaction was initiated-as evidenced by the spontaneous warming. of the mixture. The reaction mixture was then heated on the steam bath for 3 hours, while a1- lowingethyl formate and ethanol, the-volatile products ofthe reaction, to distill out. The residue was distilled under reduced pressure and the fraction boiling at 11.0.114 C. at 0.5" mm, comprising diethyl diethoxymethylsuccinate, was collected. 1

1260 g. of diethyl diethoxymethylsuccinate, a yield of 85'percent of theoretical, were obtainedhaving n =1.4303 and Analysis showed the presence of 56.09 percent carbon temperature for 2 hours, and then 1 liter of ice water'was' addedwhile stirring. The aqueous layer was separated, and was faintly acidified with-cold dilute sulfuric acid, whereupon an oil comprising diethyl l-formyl-Z-diethoxymethylsuccinate separated; The oil was-separated and the acid solution was extracted with two 200 cc. portions of ether. The ether extracts and the oil were combined, dried over anhydrous magnesium sulfate and distilled under vacuum on a steam bath to remove the ether. The residue, comprising 172g. of diethyl l-formyl-Z-diethoxy methylsuccinate, or a'yield of 89'percent of theory, was pure enough for cyclization, although for further purification the residue was distilled under vacuum, and the fraction distilling at 124 C. at 0.8 mm. pressure collected.

Diethyl 1-formyl-2-diethoxymethylsuccinate thus prepared and purified had n 1.4682 and 7.48 percent hydrogen as compared with. the" calculated 4 amounts of 55.25 percent carbon and 7.95 percent hydrogen.

EXAMPLE 2 Preparation of diethyl 3 ,4-furandicarb0xylate g. of diethyl 1-formyl-2-diethoxymethylsuccinate were added dropwise with stirring over a 5-minute period to 330 cc. of concentrated sulfuric acid. The reaction mixture was maintained at 4852? C. by periodic cooling. The mixture was kept at 50 C. for an additional 5 minutes, after which it was cooled rapidly to 0" C. and then poured over a slight excess of crushed ice. The cold solution was extracted with six 250 cc. portions ofetherl The extracts were combined, washed with 300 cc. of ice cold 3N sodium hydroxide solution, dried over anhydrous magnesium sulfate and fractionally distilled. The fraction boiling at 125127 C. at 6 mm. pressure and comprising diethyl 3,4-furandicarboxylate was collected. 78 g'., a yield of 68 percent o f'theory, of'di'ethyl 3,4'-f ura'ndicarboxylate having n =L860 were recovered.

Analysis showed the presence of 56.16 percent carbon and 6.17 percent hydrogen as compared with the calculated EXAMPLE 4 The process of Example 3 was repeated, except that liquid hydrogen fluoride was used as the cyclizing agent and the reaction mixture'was maintained at room temperature for 60 minutes.

A40 percent yield of diethyl 3,4-furandicarboxylate was obtained.

EXAMPLE 5 The process of Example 2 was repeated, except that the cyclization was carried out using zinc chloride suspended in benzene as a cyclizing agent, and the reaction mixture was refluxed for 1 hour.

A 43 percent yield of diethyl 3,4-furandicarboxylate was obtained.

. EXAMPLE 6 The process of Example 2 was repeated except-that" cyclizations were accomplished throughthe use of syrupy phosphoric acid-at areaction'temperature of 55 to 85 C., andthrough the use of a benzene solution of boro'n'trifluoride, refluxing being carried out in each case forabout 2- hours. Somewhat lower yields of diethyl 3 .4-furandicarboxylate were obtained in these runs.

EXAMPLE 7 Preparation of dimethyl 1-f0rmyl-2-dimethoxymethylsuccinate g. of sodiummethoxide were suspendedin 1-.5 liters of' anhydrous ether in a flask fitted with a reflux condenser, and a-mixture of 4 54 g. of dimethylsuccinate and 250 g. of methyl formate was added dropwise,while stirring, overa-period'ofabout one hour. Stirring'was continued for an additional 3-hour period,- after whichether. The combined ether extracts were washed with water, and dried over anhydrous magnesium sulfate. The 'etherwas then evaporated in' vacuo, and the residue distilled underrreduced pressure;

Dimethyl formylsuccinate thus prepared boiled at- 1 hours and then the solventwas removed completely in vacuo.-. The residue, comprising the ,dimethylacetal of methylformylsuccinate or dimethyl l-dimethoxymethylsuccinate, was dissolved in 600cc. of ether and washed with 5 percent aqueous sodium bicarbonate solution, followed by 25 cc. of cold 2.5 percent aqueous sodium hydroxide, to remove any unreacted dimethyl formylsuccinate. The washed, ether solution was dried over anhydrous magnesium sulfate, the ether 'was re-v movedin vacuo and the residue was-fractionally distilled under reduced pressure.

Dimethyl l-dimethoxymethylsuccinate thus prepared boiled at 125-130 C. at a pressure of 6 mm. of mercury and had n =l.43l5. A yield of 206 g., or 62 percent of theoretical, was obtained. Analysis showed the-presenc e r;49.os percent carbon and 7.33 percent hydrogen as compared with the calculated amounts of 49.08 percent carbon and 7.32'percent hydrogen. I v

To a suspension of 60 g. of sodium methylate in 1 liter of absolute ether, contained in a flask equipped with a reflux condenser, was added a mixture of 206 g. of dimethyl 1-dimethoxy-methylsuccinate and 150 g. of methyl formate. The mixture'was added'dropwise while stirring, over a period of about'l hour. Stirring was continued for about 3 hours, after which the reaction mixture was permitted to stand at room temperature for 3 days. .400 cc. of ice water were then added, the mixture was well stirred, and the aqueous layer which formed thereafter was separated off. The'aqueous slution was then acidified with cold dilute sulfuric acid and extracted with two 300 cc. portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. The ether was removed by evaporation inyacuo, leaving "a residue comprising dimethyl l-formyl- 2 dirriethoxymethylsuccinate, which was purified byfractional distillation.

Dimethyl 1-formy1-2-dimethoxyinethylsuccinate thus prepared boiled at about 125-130 C. at a pressure of 0.5 mm. of mercury and 'had n =1.4752. Analysis showed the presence of 48.07 percent carbon and 5.61 percent hydrogen as compared with the calculated amounts (148.38 'percentcarbon and 6.50 percent hydrogen. "113 g. ofmaterialsatisfactorily pure for cyclization without distillation, or 'a-yield of 48 percent of theory, were obtained.

EXAMPLE 8 Preparation of diethyl'3,4-thiophenea'icarboxylate 100 g. of diethyl 1-formyl-2-diethoxyrnethylsuccinate, prepared according to the procedure of Example 1, were mixed with 100 g. of"phospl'iorus pentasulfide and 1 liter of dry toluene. The mixture was refluxed for about 2 hours, and then allowed to stand overnight at room temperature. The resulting dark-colored solution was decanted from the insoluble material and washed well with successive quantities of water, aqueous saturated sodium bicarbonate and cold percent sodium hydroxide solution. The toluene solution was dried over magnesium sulfate, and fractionally distilled in vacuo. After removal of the toluene, the portion which distilled Off, comprising diethyl 3,4-thiophenedicarboxylate, was collected.

Diethyl 3,4-thiophenedicarboxylate thus prepared boiled at about 118-130 C. at a pressure of 1 mm. of mercury.

, EXAMPLE 9 Preparation of 3,4-thiophenedicarboxylic acid The diethyl 3,4-thiophenedicarboxylate prepared by the process of Example 8 was refluxed for 20 hours in a solution composed of 10 cc. of ethanol, 40 cc. of 12 N with r, ethanol and ether.

aqueous sodium. hydroxide and 50 cc. of water. The

reaction mixture was treated with activated carbon and was then acidified with concentrated hydrochloric acid. The 3,4-thiophenedicarboxylic acidformed in the reaction thereuponf precipitated andwas filtered off, washed well with water, and recrystallized from hot water for purification.

3,4 thiophenedicarboxylic acid thus prepared melted at about 225-226". .C.1 Analysis showed the presence of 41.80 percentcarbomand 2.44 percent hydrogen as compared with the calculated amounts .of 41.86 percent carbon and 2.34 percent hydrogen. .1

I EXAMPLE -10 Preparationhf diethyl 3,4-pyrroledicarboxylnte To 60.8 g. of diethyl 1-formyl-2-diethoxymethylsuccinate, prepared according to the method of Example 1, were added 75 g. of ammonium acetate, 5 g. of ammonium chloride, .150 cc. of acetic acid and 5 cc. of water. The mixture was refluxed for- 1 hour, and'then'the volatile portion was. removed by distillation in vacuo; The residue, comprising diethyl, 3,4-pyrroledicarboxylate, was taken up in. 500 cc. ofether. The ether solution was washed first withwater, and then with 200 cc. of ice-cold 5 .percentysodiurnhydroxide solution. The ether solution was dried overanhydrous magnesium. sulfate, and the ether. was. distilled off.. The residue was recrystallized from dilute ethanol.

Diethyl 3,4-pyrroledicarboxylate thus prepared melted atabout153-15416. Analysis showed the presence of amount of 6.63 percent. I

-' 'E XAMP L E 1-1' Diethyl 3,4 pyrroledicarboxylate was also prepared as.

follows: 55.5 .g. ,of diethyl l-formyl-2-diethoxyrnethylsuccinate were' dissolved in"'75 ;1c,c. of etherand-a solution of 4 g'. of ammonia in 25' cc. "of ethanol was added. The solvents were then removed completely in vacuo and the syrupy residue was gradually added and with stirring to cc. of concentrated sulfuric acid. The temperature of the reaction mixture'duringthis addition was kept at 45 C. The mixture was then poured over cracked ice,..whereupon crystals ofndiethyl' 3,4-pyrroledicarboxylate formedy-The product .wasfiltered ofl and washed Diethyl 3,4-pyrroledicarboxylate thus prepared melted at about 153-154 C. 18.9 g., a yield of' 49 percent of theory, were-recovered.

I, I E XA l VI PLE 12 I I Preparation ofldirhethyl 3,4-furandicarboxylate 55 g; of dimethyl*1-formyl-2-dimethoxymethylsuccinate,

prepared according "to""the' "process ofExample 7,. were added in the course of; Zito SQ'rninutes to 110 cc. of concentrated; sulfuric acid; while stirring and keepingv the tern'pratu'reof the reaction mixture'below 45 c. b e601- ing. The mixture waskept at 45 C. for a further 5 minutes, after which the solution was poured onto 500 g. of crushed ice. A crystalline precipitate, comprising dimethyl 3,4-furandicarboxylate, was formed. The precipitate was filtered OE and washed well with successive portions of cold water, saturated aqueous sodium bicarbonate, and water. On drying, the precipitate was purified by recrystallization from an ether-petroleum ether mixture.

Dimethyl 3,4-furandicarboxylate thus prepared melted at about 49-51" C. and a yield of 27 g., or 66 percent of theory, was obtained. Analysis showed the presence of 52.15 percent carbon and 4.87percent hydrogen as compared with the calculated amounts of 52.18 percent carbon and 4.3 8 percent hydrogen.

I I EXAMPLE 13 Preparation of 3,4-furandicarboxylic acid 141 g. ofdiethyl 3,4-furandicarboxylate were dissolved 1.5 g. of diethyl 3,4-pyrroledicarboxylate were refluxed for about 21 hours in a solution of 3 g. of sodium hydroxide and 30' ml. of dilute aqueous ethanol. The ethanol was removed in vacuo and the aqueous solution cooled and acidified with 7 cc. of concentrated hydrochloric acid.

The 3,4-pyrroledicarboxylic acid which precipitated was filtered off and Washed with Water. It was purified by reprecipitating it from a dilute alkaline solution with dilute hydrochloric acid. The purified 3,4-pyrroledicarboxylic acid melted at about 290-292 C. (dec.).

Analysis showed the presence of 46.73 percent carbon, 3.30 percent hydrogen and 9.11 percent nitrogen as compared with the calculated amounts of 46.46 percent carbon, 3.25 percent hydrogen and 9.03 percent nitrogen.

EXAMPLE 15 The process of Example 1 is repeated, except that dip ropyl succinate and propyl formate are used in place of diethyl succinate and ethyl formate. In this way dipropyl 1-formyl-2-dipropoxymethylsuccinate is prepared.

Likewise, the process of Example 1 is repeated using dibutyl succinate and butyl formate' in place of diethyl succinate and ethyl formate. In the same manner, dibutyl 1-formyl-2-dibutoxymethylsuccinate is formed and isolated.

EXAMPLE 16 The dipropyl 1-formyl-2-dipropoxymethylsuccinate and the dibutyl 1-formyl-2-dipropoxymethylsuccinate prepared in the previous example are each subjected to the action of concentrated sulfuric acid as set forth in Example 2.

Dipropyl 3,4-furandicarboxylate and dibutyl 3,4-furandicarboxylate, respectively, are formed.

EXAMPLE 17 The dipropyl 1-formyl-2-dipropoxymethylsuccinate and dibutyl 1-formyl-2-dibutoxymethylsuccinate prepared in Example 14 are each treated with phosphorus pentasulfide according to the method of Example 8.

Dipropyl 3,4-thiophenedicarboxylate, and dibutyl 3,4- thi'ophenedicarboxylate, respectively, are formed.

EXAMPLE l8 The dipropyl l-formyl-2-dipropoxymethylsuccinate and 8 dibutyl. 1-forrr1yl-2-dibutoxymethylsuccinatev prepared in Example 14 are each cyclized with a mixture ofamm'oniurn chloride and ammonium acetate, in acetic acid solution according to the method of Example 10.

Dipropyl 3,4-pyrroledicarboxylate and dibutyl 3,4-pyr roledicarboxylate, respectively, are formed.

We claim: 1. The process of preparing a compound represented by the formula ROOOC'G'COOR all 6H wherein R represents a lower alkyl radical, which comprises formylating a dialkoxymethyl succinic acid ester to produce a 1-formyl-2-dialkoxymethyl' succinic' acid ester having the formula ROOC%13-C-COO/R- HCOH HC(OR1)2' wherein R has the same significance as before and R1 represents a lower alkyl radical, and cycliz'ing the said formula compound by treatin'g'it with an acidic cyclizing reactant containing a sulphur atom.

2. The process according to claim 1, wherein the acidic cyclizing reactant is phosphorus pentasulfide.

3. The process which comprises treating a 1"-formyl-2- dialkoxymethyl succinic acid ester having the formula R00oo-oo00R H- 'OH- HC(OR;);" wherein R and R1 represent lower alkyl radicals, with an acidic cyclizing reactant containing a sulphur atom to produce' a compound having the formula ROOCC-QCOOR I HO H wherein R has the same significance as before.

4. The process according to claim 3, wherein the acidic cyclizing reactant is phosphorus pentasulfide.

5. The process which comprises heating a l-formyl-Z- dialkoxymethyl succinic acid ester having the formula R0 OCC--OHCOOR in which R and R1 represent lower alkyl radicals, with an' acidic cyclizing reactant containing a sulphur atom, and hydrolyzing the ester groups of said compound to produce a compound having the formula No references cited. 

1. THE PROCESS OF PREPARING A COMPOUND REPRESENTED BY THE FORMULA 